Endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes its subendothelial retention in vascular wall

Oxid Med Cell Longev. 2014;2014:823071. doi: 10.1155/2014/823071. Epub 2014 Apr 10.

Abstract

Oxidized low density of lipoprotein (oxLDL) is the major lipid found in atherosclerotic lesion and elevated plasma oxLDL is recognized to be a risk factor of atherosclerosis. Whether plasma oxLDL could be transported across endothelial cells and initiate atherosclerotic changes remains unknown. In an established in vitro cellular transcytosis model, the present study found that oxLDL could traffic across vascular endothelial cells and further that the regulation of endogenous ceramide production by ceramide metabolizing enzyme inhibitors significantly altered the transcytosis of oxLDL across endothelial cells. It was found that acid sphingomyelinase inhibitor, desipramine (DES), and de novo ceramide synthesis inhibitor, myriocin (MYR), both decreasing the endogenous ceramide production, significantly inhibited the transcytosis of oxLDL. Ceramidase inhibitor, N-oleoylethanolamine (NOE), and sphingomyelin synthase inhibitor, O-Tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609), both increasing the endogenous ceramide production, significantly upregulated the transcytosis of oxLDL. In vivo, injection of fluorescence labeled oxLDL into mice body also predisposed to the subendothelial retention of these oxidized lipids. The observations provided in the present study demonstrate that endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes the initiating step of atherosclerosis-the subendothelial retention of lipids in vascular wall.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged-Ring Compounds / pharmacology
  • Ceramidases / antagonists & inhibitors
  • Ceramidases / metabolism
  • Ceramides / metabolism*
  • Desipramine / pharmacology
  • Endocannabinoids / pharmacology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Ethanolamines / pharmacology
  • Fatty Acids, Monounsaturated / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Norbornanes
  • Oleic Acids / pharmacology
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingosine N-Acyltransferase / antagonists & inhibitors
  • Sphingosine N-Acyltransferase / metabolism
  • Thiocarbamates
  • Thiones / pharmacology
  • Transcytosis / drug effects
  • Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors
  • Transferases (Other Substituted Phosphate Groups) / metabolism
  • Up-Regulation / drug effects

Substances

  • Bridged-Ring Compounds
  • Ceramides
  • Endocannabinoids
  • Ethanolamines
  • Fatty Acids, Monounsaturated
  • Lipoproteins, LDL
  • Norbornanes
  • Oleic Acids
  • Thiocarbamates
  • Thiones
  • oxidized low density lipoprotein
  • N-oleoylethanolamine
  • tricyclodecane-9-yl-xanthogenate
  • Sphingosine N-Acyltransferase
  • Transferases (Other Substituted Phosphate Groups)
  • phosphatidylcholine-ceramide phosphocholine transferase
  • Sphingomyelin Phosphodiesterase
  • Ceramidases
  • Desipramine
  • thermozymocidin